Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, 21521 Alexandria, Egypt.
Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
Bioorg Chem. 2021 Oct;115:105208. doi: 10.1016/j.bioorg.2021.105208. Epub 2021 Jul 26.
An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC = 0.43-1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d, as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.
设计、合成了一系列新合成的基于噻吩并[3,2-d]嘧啶的衍生物和噻吩并三唑嘧啶与一些药效团抗癌片段的杂合体，并通过 MTT 测定法，以厄洛替尼和pictilisib 为参考标准，评估它们对 MCF-7 和 MDA-MB-231 乳腺癌细胞系的体外增殖活性。总的来说，许多化合物具有相当的增殖活性（IC = 0.43-1.31 µM）。一些测试的化合物，即 3c、5b、5c、9d、10、11b 和 13，对两种细胞系均表现出显著的增殖活性。同时，化合物 2c-e、3b、4a、5a、9c 和 15b 对 MCF-7 细胞表现出明显的选择性，而化合物 2b、3a、4b、6a-c、7、8、9b 和 12 对 MDA-MB-231 细胞表现出相当的选择性。通过筛选对 MCF-7 和/或 MDA-MB-231 细胞具有 EGFR 和 ARO 抑制活性的最有效化合物，用厄洛替尼和来曲唑分别作为参考标准，为其抗癌活性提供了进一步的机制证据。结果表明，一般来说，测试的化合物是更好的 EGFRIs 而不是 ARIs。此外，在所有测试的化合物中，用 4-氟苯肼衍生物 2d 处理 MCF-7 乳腺癌细胞系样本时，caspase-9 水平显著升高，表现出最高的激活作用。在处理 MDA-MB-231 乳腺癌细胞系样本时，发现 11b 能高度诱导 caspase-9 水平，从而诱导细胞凋亡。还对活性化合物进行了细胞周期分析和 Annexin V-FITC/PI 检测，结果表明，所有测试的化合物均诱导 preG1 凋亡和 G2/M 期细胞周期阻滞。作为 ARO 抑制剂的化合物 9d 被观察到下调 MCF-7 细胞中 HSP27 和 p-ERK 的下游信号蛋白。此外，化合物 11b 下调 EGFR 表达以及下游信号蛋白 p-AKT。EGFR 和 ARO 酶的对接实验支持了它们的体外结果。因此，噻吩并三唑嘧啶 11b 和 12 显示出良好的 EGFR 抑制作用，噻吩并[3,2-d]嘧啶衍生物 3b 和 9d 表现出最好的 ARO 抑制活性，可以作为新的候选抗乳腺癌药物，需要进一步开发。
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